Toxicity valproate

Valproate may increase concentrations of phenobarbital, etho-suximide, and the active 10,11-epoxide metabolite of carba-mazepine, increasing the risk of toxicity. Valproate may also raise lamotrigine levels, increasing the risk of rash. 

Felbamate can raise valproate serum levels causing toxicity. Valproate may slightly decrease the clearance of felbamate. 

R. H. Lavey, and J. K. Penny (eds.), Idiosyncratic Reactions to Valproate Clinical Risk Patterns and Mechanism of Toxicity, Raven Press, New York, 1991, pp. 19-24. 

The short chain fatty acids include butyrate derivatives Hke phenylbu-tyrate, AN-9 (pivaloyloxymethyl butyrate) and valproate. Unfortimately, these compounds have poor potency and pharmacokinetic properties, including short half-life. Numerous Phase I studies with phenylbutyrate, in various oral and intravenous schedules [118-120] have been performed, with neurological toxicity at higher doses being reported. AN-9 showed initial promise in a Phase I study, where the MTD was not reached [121]. The subsequent Phase II study in nonsmall cell lung cancer in 47 patients resulted in fatigue, nausea and dysgeusia as common toxicities. Three partial responses (PR)... 

Medium chain acyl-CoA dehydrogenase deficiency and fatal valproate toxicity. 

Sodium valproate is converted to valproic acid in the intestine and the acid is absorbed. Absorption may be delayed by food or by enteric-coated tablets. Valproic acid has a low volume of distribution and high plasma protein binding. In the elderly there is a risk for increased free valproic acid concentrations requiring lower doses and plasma concentrations at the lower therapeutic range. However it should be realized that these plasma concentrations do not correlate very well with the therapeutic or toxic effects and careful observation for symptoms is mandatory. 

A related issue is the patient s ability to metabolize and eliminate drugs adequately. For example, lithium is excreted entirely by the kidneys, and if a patient suffers from significantly impaired renal function, high, potentially toxic levels could develop on standard doses. Although the dose could be adjusted to compensate for the decrease in drug clearance, it might be more appropriate to choose another mood stabilizer such as valproate or carbamazepine, because they are primarily metabolized through the liver. 

Goulden KJ, Dooley JM, Camfield PR, et al. Clinical valproate toxicity induced by acetylsalicylic acid. Neurology 1987 37 1392-1394. 

The use of drug plasma levels to effect optimal clinical response and to minimize adverse or toxic effects is standard practice in general medicine (e.g., phenytoin, digoxin), as well as in psychiatry (e.g., lithium, tricyclic antidepressants, valproate see Chapter 3). The theoretical basis for plasma level monitoring rests on several factors, including ... 

In addition, an open-label study was conducted examining the efficacy of valproate in ten adolescents with chronic temper outbursts and mood lability ( 193). The authors report that valproate was associated with improvement in all subjects, that discontinuation led to relapse, and that there was subsequent improvement on rechallenge in five of six subjects. Although encouraging, these data are modest in terms of both the numbers and design and must be balanced against the risk of toxicity (e.g., hepatic and pancreatic) with valproate in children. 

Valproate is well absorbed after an oral dose, with bioavailability greater than 80%. Peak blood levels are observed within 2 hours. Food may delay absorption, and decreased toxicity may result if the drug is given after meals. 

Phenobarbital Enhances phasic GABAa receptor responses reduces excitatory synaptic responses Nearly complete absorption not significantly bound to plasma proteins peak concentrations in Vi to 4 h no active metabolites tjy2 varies from 75 to 125 h Generalized tonic-clonic seizures, partial seizures, myoclonic seizures, generalized seizures, neonatal seizures, status epilepticus Toxicity Sedation, cognitive issues, ataxia, hyperactivity Interactions Valproate, carbamazepine, felbamate, phenytoin, cyclosporine, felodipine, lamotrigine, nifedipine, nimodipine, steroids, theophylline, verapamil, others... 

Ethosuximide Reduces low threshold Ca2+ currents (T-type) Well absorbed orally, with peak levels in 3-7 h not protein-bound completely metabolized to inactive compounds tjy2 typically 40 h Absence seizures Toxicity Nausea, headache, dizziness, hyperactivity Interactions Valproate, phenobarbital, phenytoin, carbamazepine, rifampicin... 

Valproate toxicity is manifested as fatty liver, but what is the underlying mechanism ... 

Valproate is often associated with low carnitine concentrations and occasionally with true carnitine deficiency, especially in young children with neurological disabilities taking several anticonvulsants. The condition is usually asymptomatic, but it can occasionally cause significant toxicity (1185). 

Kay JD, Hilton-Jones D, Hyman N. Valproate toxicity and ornithine carbamoyltransferase deficiency. Lancet 1986 2(8518) 1283 1. 

Coulter DL. Carnitine, valproate, and toxicity. J Child Neurol 1991 6(1) 7-14. 

Porubek DJ, Grillo MP, Olsen RK, et al. Toxic metabolites of valproic acid inhibition of rat liver acetoacetyl-CoA thiolase by 2-n-propyl-4-pentenoic acid (A4-VP A) and related branched chain carboxylic acids. In Levy RH, Penry JK, eds. Idiosyncratic Reactions to Valproate Clinical Risk Patterns and Mechanisms of Toxicity. New York Raven Press, 1991 53-58. 

Consider the difference in response to drugs between older and younger people. Treatment should reflect biological age (rather than chronological). Pharmacokinetics, pharmacodynamics, tolerability, adverse reactions, economy and patient choice will all influence therapy chosen. Most commonly, car-bamazepine or sodium valproate are chosen for older people as their effects in older people are well documented. Both show a favourable balance of safety, efficacy and economy. Phenytoin is less preferable because of drug interactions, adverse effects and potential for toxicity (zero order kinetics). 

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